The local control of cancer's recurrence or relapse constitutes a crucial step of anti-cancer treatment following surgery and radiotherapy steps. Post-operative radiotherapy is used in several indications to treat the tumor bed once tumorectomy has been performed in order to improve rates of local control and thus reduce, and ideally avoid, tumor recurrences. A recent meta-analysis of the Early Breast Cancer Trialists' Collaborative Group stressed the importance of reducing local breast tumor recurrences, because one breast cancer death could be avoided for every four local recurrences avoided. According to the authors of “Customized computed tomography-based boost volumes in breast-conserving therapy: use of three-dimensional histologic information for clinical target volume margins” [IJROBP, 75(3): 757-763 (2009)], one method to improve local control is to increase the radiation dose the tumor bed is exposed to (i.e., boost irradiation). The authors add that this effect could be further increased by improving the delineation of the tumor bed (i.e., the target volume the boost irradiation should specifically target).
The International Commission on Radiation Units and Measurements defines the Gross Tumor Volume (GTV) as the gross demonstrable extent and location of a malignant growth. For the adjuvant breast radiotherapy (the surgical step is followed by a radiotherapy step), the GTV has been excised with a variable margin of tissue, leaving a cavity. The cavity is not the GTV, but related to it. The cavity walls are referred to, somewhat loosely, as the tumor bed [“Target volume definition for external beam partial breast radiotherapy: clinical, pathological and technical studies informing current approaches,” Radiotherapy and Oncology, 94: 255-263 (2010)].
In clinical practice, accurately identifying the tumor bed is challenging and a high rate of inter-observer variability in tumor bed contouring is frequently reported, especially in poorly visualized resection cavities [“Excised and Irradiated Volumes in Relation to the Tumor size in Breast-Conserving Therapy,” Breast Cancer Res. Treat., 129:857-865 (2011)]. The irradiated postoperative volume (as delineated on the radiotherapy planning CT scan before the start of radiotherapy) in patients treated with breast-conserving therapy is not, for most of the cases, clearly visible and a cavity visualization score is frequently used to assess the quality of the irradiated postoperative volume identification.
Likewise, for prostate cancers, the EORTC Radiation Oncology Group has made recommendations for target volume definition in post-operative radiotherapy, presenting guidelines for standardization of the target volume definition and delineation as well as standardization of the clinical quality assurance procedures; the authors of “Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group” [Radiotherapy & Oncology, 84: 121-127 (2007)] in particular referred to a study where a high inter-observer variability of target volume delineation in postoperative radiotherapy for prostate cancer was observed when performed by five (5) distinct radiation oncologists for eight (8) distinct patients. (The CTV varied between the physicians from 39 to 53 cm3 for the patient corresponding to the smallest variation and from 16 to 69 cm3 for the patient corresponding to the largest variation.)
A study to evaluate the accuracy of a boost technique, reported in “Improving the definition of the tumor bed boost with the use of surgical clips and image registration in breast cancer patients” [Int. J. Radiation Oncology Biol. Phys., 78(5): 1352-1355 (2010)], shows that the use of radiopaque clips during tumorectomy, typically 3 or more clips, increases the accuracy of the tumor bed delineation (see FIG. 1). However, questions of the accuracy of CT/clip-based TB delineation remain. Clips only define points located on the excision cavity walls such that the remaining tumor tissue-excision cavity interface must be derived by interpolation, taking into account tissue density and distortion.
Interestingly, a report on the magnitude of volumetric change in the post-lumpectomy tumor bed has demonstrated significant tumor bed volume changes before and during radiation therapy or radiotherapy (RT) [“The dynamic tumor bed: volumetric changes in the lumpectomy cavity during breast conserving therapy” Int. J. Radiation Oncology Biol. Phys., 74(3):695-701 (2009)]. Thirty-six (36) patients were enrolled in the study, with Tis (10), T1 (24) and T2 (2) breast tumors. Thirty (30) patients received a whole breast irradiation after lumpectomy followed by a boost dose of 10 Gy. Six (6) patients were treated with partial breast irradiation. Treatment planning CT scans of the breast were obtained shortly after surgery, before the start of the whole breast irradiation for treatment planning and before delivery of the tumor bed boost. Patients who were treated with partial breast irradiation received only a scan postoperatively and a scan before tumor bed treatment.
During the interval between the postoperative scan and second scan (median interval, 3 weeks), the tumor bed volume decreased by a median of 49.9%. Between the planning scan and the boost scan (median interval, 7 weeks), the median tumor bed volume decreased by 44.6%.
A subgroup of eight (8) patients, who experienced a delay (median interval, 23 weeks) between surgery and RT because of planned chemotherapy, had a median reduction of the tumor bed volume of 60.3% during the interval between the postoperative scan and planning scan. When this magnitude and rate-of-change data were evaluated in the context of the entire patient set, the observed results suggested that the tumor bed volume decreased more rapidly in the weeks immediately after surgery and then attained a relative plateau.
According to the authors, the impact of large volumetric change on planning volume, dosimetry, or clinical parameters such as local control or cosmetic outcome is an important area for future research, as theoretically, if a single planning scan is used to plan the boost clinical target volume (CTV) in a patient with a tumor bed that shrinks dramatically during the course of RT, the surrounding normal tissues receive unnecessary additional radiation that could yield poorer cosmetic outcomes and more late undesirable effects. Conversely, if a single planning scan is performed long after surgery, the reduced tumor bed volume could actually result in underestimating the true tumor bed or the area of surgical tumor contamination.
WO 2011/084465 relates to stabilizing and visualizing tissue gaps left by surgical removal of cancerous tissues. According to the inventors, a conformal filling approach is a considerable improvement over the use of clips, which provide poor resolution of the site's margins. The described implants may be formulated to be stable until no longer needed, and then biodegrade. According to WO 2011/084465, the implantation of the hydrogel leads to an increase of the mean cavity volume. Therefore, when using standard margins, the hydrogel tends to increase normal tissue radiation doses. A reduced margin expansion is thus required in order to decrease normal tissue radiation doses.
As easily understandable from the above, there remains a clear need to improve the post-surgery tumor bed delineation.